The Transmembrane Protein 16A Ca2+-activated Cl- Channel in Airway Smooth Muscle Contributes to Airway Hyperresponsiveness

被引:65
|
作者
Zhang, Cheng-Hai [1 ,2 ,3 ]
Li, Yinchuan [3 ]
Zhao, Wei [1 ,2 ]
Lifshitz, Lawrence M. [4 ,5 ]
Li, Hequan [6 ]
Harfe, Brian D. [7 ]
Zhu, Min-Sheng [1 ,2 ]
ZhuGe, Ronghua [3 ,4 ]
机构
[1] Nanjing Univ, Model Anim Res Ctr, Nanjing 210008, Jiangsu, Peoples R China
[2] Nanjing Univ, MOE Key Lab Model Anim Dis Study, Nanjing 210008, Jiangsu, Peoples R China
[3] Univ Massachusetts, Sch Med, Dept Microbiol & Physiol Syst, Worcester, MA 01655 USA
[4] Univ Massachusetts, Sch Med, Biomed Imaging Grp, Worcester, MA USA
[5] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA USA
[6] Zhejiang Univ, Sch Med, Affiliated Hosp 1, Dept Resp Dis,Coll Med, Hangzhou 310003, Zhejiang, Peoples R China
[7] Univ Florida, Sch Med, Gainesville, FL USA
基金
中国国家自然科学基金;
关键词
TMEM16A; airway smooth muscle; airway hyperresponsiveness; NIFLUMIC ACID; CA2+ SPARKS; MUCUS OVERPRODUCTION; TMEM16A; ASTHMA; CURRENTS; CONDUCTANCE; CANINE; EXPRESSION; K+;
D O I
10.1164/rccm.201207-1303OC
中图分类号
R4 [临床医学];
学科分类号
1002 ; 100602 ;
摘要
Rationale Asthma is a chronic inflammatory disorder with a characteristic of airway hyperresponsiveness (AHR). Ca2+-activated Cl- [Cl-(Ca)] channels are inferred to be involved in AHR, yet their molecular nature and the cell type they act within to mediate this response remain unknown. Objectives: Transmembrane protein 16A (TMEM16A) and TMEM16B are Cl-(Ca) channels, and activation of Cl-(Ca) channels in airway smooth muscle (ASM) contributes to agonist-induced airway contraction. We hypothesized that Tmem16a and/or Tmem16b encode Cl-(Ca) channels in ASM and mediate AHR. Methods: We assessed the expression of the TMEM16 family, and the effects of niflumic acid and benzbromarone on AHR and airway contraction, in an ovalbumin-sensitized mouse model of chronic asthma. We also cloned TMEM16A from ASM and examined the Cl- currents it produced in HEK293 cells. We further studied the impacts of TMEM16A deletion on Ca2+ agonist-induced cell shortening, and on Cl-(Ca) currents activated by Ca2+ sparks (localized, short-lived Ca2+ transients due to the opening of ryanodine receptors) in mouse ASM cells. Measurements and Main Results: TMEM16A, but not TMEM16B, is expressed in ASM cells and its expression in these cells is up-regulated in ovalbumin-sensitized mice. Niflumic acid and benzbromarone prevent AHR and contraction evoked by methacholine in ovalbumin-sensitized mice. TMEM16A produces Cl-(Ca) currents with kinetics similar to native Cl-(Ca) currents. TMEM16A deletion renders Ca2+ sparks unable to activate Cl-(Ca) currents, and weakens caffeine- and methacholine-induced cell shortening. Conclusions: Tmem16a encodes Cl-(Ca) channels in ASM and contributes to Ca2+ agonist-induced contraction. In addition, up-regulation of TMEM16A and its augmented activation contribute to AHR in an ovalbumin-sensitized mouse model of chronic asthma. TMEM16A may represent a potential therapeutic target for asthma.
引用
收藏
页码:374 / 381
页数:8
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